The development of daratumumab and isatuximab, anti-CD38 monoclonal antibodies (MoABs), has created a new class of agents for the treatment of multiple myeloma (MM). These have proven efficacy both as single-agent monotherapy and in combination with proteasome inhibitors (PIs) and/or immunomodulatory drugs (IMiDs).

Notably, anti-CD38 MoABs have significant activity in patients who have been heavily pre-treated and are refractory/resistant (RR) to PIs and IMiDs. Daratumumab was the first anti-CD38 MoAB approved by the U.S. Food and Drug Administration, initially in combination and now as monotherapy in specific settings.1 Isatuximab is another anti-CD38 MoAB, currently being investigated in a phase III trial (NCT02990338), which recently met its primary endpoint of improving progression-free survival (PFS) in patients with RRMM in combination with pomalidomide and dexamethasone.2

Since the outcomes of patients who are refractory to these MoABs has not, to date, been investigated, Ujjawal H Gandhi, Vanderbilt University Medical Center, Nashville, TN, and colleagues conducted the, “monoclonal antibodies in multiple myeloma: outcomes after therapy failure” (MAMMOTH) study. The results were recently published in Leukemia. It was hypothesized that patients who are refractory to anti-CD38 MoABs would have very few effective treatment options and would represent a new population for whom novel treatments are required.3

Study design and patient characteristics

This retrospective study identified patients with active MM who were refractory to daratumumab or isatuximab as a single-agent or in combination (index regimen). The index regimen must have been part of the management of RRMM, have been used for at least 4 weeks, and with evidence of progressive disease (PD). The time between a diagnosis of MM and refractoriness to CD38 MoAB was termed T0.

Based on their refractory status, patients (N = 275) were classified into three groups:

Conclusion

Firstly, the MAMMOTH study has identified a group of patients for whom there is a significant unmet need for effective treatments. These patients, who are refractory to CD38 MoABs, regardless of sensitivity to PIs and IMiDs, have an unfavorable prognosis. This study represents a benchmark for the comparison of outcomes of newer clinical trials involving novel therapies such as CAR T-cell therapies, bispecific antibodies and antibody-drug conjugates.

Secondly, the analysis of outcomes to subsequent therapy regimens provides some evidence for clinical decisions in this setting. Carfilzomib-based regimens provided the most favorable PFS and OS rates whilst daratumumab-IMiD combination regimens may provide better results in patients refractory to single-agent CD38 MoAB.

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